Plasticity in the hippocampus plays a role in learning and memory, and in neurobiological responses to stress and antidepressant drug action. A significant increase in neuron and glial cell density and a decrease in neuronal soma size has been detected in hippocampus of 19 subjects with major depressive disorder (MDD). The changes in density in MDD were independent of suicide or gender. It is hypothesized that a decrease in hippocampal neuropil, in response to diminished markers of neural growth and synaptic connection, resulting in an increase in neuronal and glial density, is the microscopic basis for the histopathology of the hippocampus in MDD. Aims 1-3 examine the hypothesis that in MDD there is a decrease in hippocampal neuropil, as compared to normal controls. Aims 4-5 examine the hypothesis that there will be diminished markers of neural growth and synaptic connection in the hippocampus in MDD. In Aim 1, stereological experiments in MDD will estimate the total cell number and density of neurons and gila and the corresponding volume throughout the entire hippocampus. In Aim 2, the Golgi silver method will be used to measure spine density, number of dendritic branch points and total length of apical and basal dendritic trees of pyramidal neurons in hippocampal CA1 & CA3 subfields in MDD. In Aim 3, the density and size of glial fibrillary acidic protein (GFAP) -immunoreactive cell bodies, and the areal fraction occupied by GFAP-immunoreactivity in astrocytes will be measured in the hippocampus in MDD. In Aim 4, experiments are designed to stereologically estimate the total immunoreactive cell number and packing density of markers of synaptic plasticity [brain derived neurotrophic factor (BDNF), growth associated protein-43 (GAP-43) and polysialylated-nerve cell adhesion molecule (PSA-NCAM)] throughout the hippocampus in MDD. In Aim 5, experiments will be carried out to quantify mRNA for BDNF and GAP-43 in CA3 and CA4 of the rostral hippocampus in MDD. It is predicted that the hypothesized decrease in expression of BDNF and GAP-43 protein in Aim 4 will be secondary to related decreases in gene expression in the hippocampus. Cellular changes detected in MDD postmortem may underlie hippocampal atrophy detected by some in living subjects with MDD.